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Month: January 2023

Cystic Fibrosis: A New Therapeutic Avenue Thanks to Research Into an Edible Mushroom

Posted on by Graziella Cara

Lepista flaccida, champignon comestible

Lepista flaccida, an edible mushroom found in the northern hemisphere, was the focus of research by French teams into ways of correcting certain genetic mutations known as nonsense mutations. © MNHN/CNRS – Christine Bailly

A molecule obtained from an edible mushroom could open up therapeutic avenues for patients with cystic fibrosis, the most frequent rare genetic disease. A team led by Fabrice Lejeune, Inserm researcher at the Cancer Heterogeneity, Plasticity and Resistance to Therapies laboratory[1] (Inserm/ CNRS/ Université de Lille/Institut Pasteur de Lille/University Hospital Lille) tested the effects of 2,6-diaminopurine (DAP), one of the active principles contained in the Lepista flaccida mushroom, in different experimental models of the disease.  The scientists have shown that this molecule could be of therapeutic value in patients with cystic fibrosis linked to a particular type of mutation known as a nonsense mutation. Their findings have been published in Molecular Therapy.

Around 6,000 people in France have cystic fibrosis, a genetic disease that primarily affects digestive and respiratory function, and has a 40 to 50-year life expectancy. Nevertheless, therapeutic innovations have improved patient prognosis in recent years. Treatments are now available for the vast majority of patients – those whose disease is caused by the delta F508 mutation of the CFTR gene. In these patients, the CFTR protein (coded by the CFTR gene) is present in small amounts but is dysfunctional. The molecules currently available are able to correct this dysfunction and significantly improve their clinical symptoms.

However, they are not effective in the 10% of patients for whom the protein is completely absent, as is the case when the disease is linked to a nonsense mutation (see box).

Nonsense Mutations and Genetic Diseases

DNA is made up of nucleotides, organic compounds that code the amino acids implicated in the synthesis of the proteins needed for the body to function correctly. In practice, nonsense mutations introduce a “stop codon” in the mutated gene, i.e. a sequence of nucleotides that brings the synthesis of the corresponding protein to a premature halt. From that point, the protein is no longer produced, leading to the onset of the clinical symptoms of the disease.

Identifying ways to correct nonsense mutations is therefore an important challenge for researchers studying genetic diseases and who hope to develop new therapeutic options against cystic fibrosis.

In this context, Inserm researcher Fabrice Lejeune and his team[2] made an innovative finding in 2017 by showing that extracts of a commonplace edible mushroom known as Lepista flaccida could repair nonsense mutations in three cell lines isolated from cystic fibrosis patients. A few years later in 2020, Lejeune and his team published a study identifying the active principle in the mushroom that is capable of correcting the nonsense mutations associated with the UGA stop codon – the most common of the three stop codons of the human genetic code. The active principle concerned was 2,6 diaminopurine (DAP).

In their latest research, the scientists tested the effects of this molecule in four experimental models of cystic fibrosis: animal models of the disease, developed in the laboratory; cell lines; patient cells and organoids. This diversity of models makes it possible to be as close as possible to what is happening in the patient’s body, in order to assess the potential therapeutic benefits they may obtain.

The results obtained by the team suggest that DAP corrects the nonsense mutation in the different models studied, by re-establishing protein production and effectively restoring the function of the mutated gene.

In clinical terms, this results in an improvement in symptoms in animals. The treatment with DAP makes it possible to restore CFTR expression in the lungs and intestines as well as the function of this protein, significantly reducing the premature mortality observed prior to administration of this molecule.

In addition, the research team has also shown that DAP can be given orally and that it is distributed effectively throughout the body for around two hours. These characteristics are also a positive point when it comes to considering DAP as a serious therapeutic avenue, as this means that we could reach all the tissues in the body while limiting the duration of exposure to the molecule, thereby reducing possible side effects.

“DAP could represent the first molecule capable of providing therapeutic benefit to patients with cystic fibrosis linked to a nonsense mutation and, more broadly, to patients with a genetic disease linked to a nonsense mutation,” explains Lejeune.

These results pave the way for a potential clinical trial in the coming years to test the efficacy of the molecule in patients. Before this, the goal is to develop the best possible formulation for the drug and to carry out toxicity tests to ensure its safety in humans. In the shorter term, the teams also want to test DAP in models of other rare genetic diseases, particularly Duchenne muscular dystrophy and Rett’s syndrome, for which over 60% of patients are affected by nonsense mutations.

 

[1] Cancer Heterogeneity, Plasticity and Resistance to Therapies laboratory at the ONCOLille institute

[2]The following research units also contributed to these findings: Communication Molecules and Adaptation of Micro-organisms (CNRS/MNHN), Biometrics and Evolutional Biology Laboratory (CNRS/Université Claude Bernard Lyon 1/VetAgro Sup), Lille Platforms in Biology and Health (PLBS) (CNRS/University Hospital Lille/Inserm/Institut Pasteur Lille/Université Lille), Strasbourg Platform for Integrative Biological Chemistry (CNRS/Université de Strasbourg).

Discovery of a circovirus involved in human hepatitis

Posted on by Graziella Cara

circovirus_ illustration

© Adobe Stock

Scientists from the Institut Pasteur, Necker-Enfants Malades Hospital (AP-HP), Inserm in the Imagine Institute, Université Paris Cité and the Alfort National Veterinary School (EnvA) have identified a previously unknown species of circovirus, provisionally named human circovirus 1 (HCirV-1). Circoviruses are a family of small, highly resistant DNA viruses that were initially identified in 1974 in various animal species, where they can cause respiratory, renal, dermatological and reproductive problems. HCirV-1 is a novel virus that is distant from known animal circoviruses. It was shown to be implicated in damage to the liver of a patient undergoing immunosuppressive treatment. This discovery of the first circovirus in humans, linked to hepatitis, was published in the journal Emerging Infectious Diseases on January 3, 2023.

Although the transmission of animal viruses to humans is regularly reported in the scientific literature, it is rare for a novel virus to be identified in a patient in Europe. But as part of a recent study, scientists and physicians have identified the first circovirus involved in human hepatitis.

“The patient had unexplained chronic hepatitis, with few symptoms. She had received a heart-lung transplant 17 years earlier and had been monitored regularly since. We had access to a large number of samples over several years and were therefore able to identify this novel virus, which was completely unexpected,” explains Marc Eloit, last author of the study, Head of the Institut Pasteur’s Pathogen Discovery laboratory and a Professor of Virology at the Alfort National Veterinary School (EnvA). His laboratory specializes in the identification of pathogens in patients suspected of severe infection of unknown cause.

In March 2022, in collaboration with the Department of Clinical Microbiology at Necker-Enfants Malades Hospital (AP-HP), the pathological tissue samples of this 61-year-old female patient receiving immunosuppressive treatment, whose hepatitis had no identifiable cause, were sequenced to search for microbial sequences. The RNA (ribonucleic acid) sequences extracted from the tissues were analyzed and compared with those of known microbes.

“The aim is to identify sequences of interest among all the sequences obtained, which is like searching for a needle in a haystack!” continues the scientist Marc Eloit.

These thousands of RNA sequences were analyzed in parallel using mNGS (metagenomic next-generation sequencing) high-throughput sequencing techniques and sophisticated algorithms. After ruling out common etiologies, the analysis led to the identification of a previously unknown species of circovirus, provisionally named human circovirus 1 (HCirV-1). No other viral or bacterial sequence was found.

The involvement of HCirV-1 in the hepatitis was then demonstrated by analyzing samples taken from the patient in previous years as part of her post-transplant treatment. The results showed that the HCirV-1 viral genome was undetectable in the blood samples from 2017 to 2019, then that its concentration peaked in September 2021. Viral replication in liver cells was demonstrated (2 to 3% of liver cells were infected), pointing to the role of HCirV-1 in liver damage: once the virus has used the resources in the liver cell to replicate, it destroys the cell.

From November 2021 onwards, following antiviral treatment, the patient’s liver enzymes returned to normal levels, indicating the end of hepatic cytolysis.

Diagnosing hepatitis of unknown etiology remains a major challenge, as shown by the cases of acute hepatitis reported in children in the United Kingdom and Ireland last April and signaled by WHO.

“We need to know the cause of the hepatitis, and especially whether or not it is viral, to be able to offer suitable treatment and monitor patients effectively. The identification of this novel virus that is pathogenic in humans, and the development of a test that can be performed by any hospital laboratory, offers a new tool for diagnosing and monitoring patients with hepatitis,” stresses Anne Jamet from the Department of Clinical Microbiology at Necker-Enfants Malades Hospital (AP-HP), who is also affiliated with Inserm and co-last author of the study.

Although some circoviruses are pathogenic for animals and vaccines can be administered, especially in pigs, this is the first known circovirus to be pathogenic for humans. The patient’s symptoms remained mild; the virus was able to be identified because she was being closely monitored following her combined transplant. The origin of the virus – whether it is circulating in humans or of animal origin – has yet to be identified, and the source of infection (contact, food, etc.) remains unknown. Following their discovery, the scientists developed a specific PCR test that is now available for etiological diagnosis of hepatitis of unknown origin. A serological test is also being developed.

“These results show the value of this type of sequencing analysis in identifying novel or unexpected pathogens. It is always important for clinicians to know whether or not an infection is viral so that they can adapt the treatment accordingly. It is also crucial to be able to identify a novel pathogen when an infection remains unexplained and to develop a diagnostic test, because any new case of human infection with an emerging pathogen may potentially signal the start of an outbreak,” concludes Marc Eloit. The test is available for the medical community and can now be easily performed for other cases of unexplained hepatitis.

Dengue and Zika Viruses: Towards a Better Understanding of the Mechanisms of Transmission

Posted on by Graziella Cara

moustique Aedes aegypti

The Aedes aegypti mosquito is the main vector of dengue, Zika virus infection, chikungunya, and yellow fever. © Adobe Stock

Aedes mosquitoes are the principal vectors of dengue and other arboviruses, including Zika, for which no vaccines or antiviral treatments currently exist. Understanding the factors that influence the transmission of arboviruses from mosquitoes to humans is therefore a priority because it could guide the implementation of public health measures that could limit or even prevent epidemics. In a new study, a team of researchers from Inserm, CNRS and Université de Strasbourg at the Institute of Molecular and Cellular Biology, in collaboration with the Federal University of Minas Gerais in Brazil, described the virome (the totality of the viruses) present in 800 mosquitoes collected in six countries across four continents. The scientists show that out of the 12 viruses identified, two of them do not infect humans but increase the potential for transmission of dengue and Zika. The mechanism involved reveals the existence of a new cellular factor hijacked by arboviruses in mosquitoes. Their findings have been published in Nature Microbiology.

Among the infectious viral diseases transmitted by mosquitoes, the frequency of dengue is the fastest growing worldwide, and is currently responsible for 400 million new infections each year. This increase in the number of cases of dengue, as well as other diseases caused by viruses transmitted by mosquitoes (arthropod-borne viruses), such as Chikungunya and Zika, reflects the geographic expansion of the principal vector mosquitoes, Aedes aegypti and A. albopictus, particularly due to globalization and climate change.

The virological surveillance of adult Aedes mosquitoes using metagenomic analysis[1] can lead to the early identification of circulating arboviruses and thus contribute to improving public health measures. In addition to arboviruses, these surveillance methods have identified a large number of insect-specific viruses in Aedes mosquitoes. Although they do not infect mammals, these viruses are likely to impact the dynamics of arbovirus transmission to humans.

This is the context for the research by a team of scientists from Inserm, CNRS and Université de Strasbourg, in which they characterized the full virome of Aedes mosquitoes on a global scale.

Using a high-throughput RNA sequencing technique[2] coupled with bioinformatics analysis according to a method developed in their laboratory, the researchers made an inventory of the viruses present in Aedes mosquitoes worldwide. They worked with a network of collaborators, the majority of whom are participating in the European consortium ZIKAlliance[3], to collect over 800 mosquitoes at 12 different sites in six countries across four continents. This enabled them to identify 12 circulating viruses, present in these mosquitoes, five of which had previously never been described.

Two of these 12 viruses, Phasi Charoen-like virus (PCLV) and Humaita Tubiacanga virus (HTV)[4], attracted the researchers’ attention because of their high levels of prevalence (they were present in over half of the samples). These two viruses were either not present or present only to a small extent in the samples from Africa, where there are few cases of dengue, in comparison with Asia or South America, where there are many.

To find out whether PCLV and HTV could affect the transmission of dengue, the scientists looked at Caratinga, a small city in south-east Brazil, where dengue is endemic and for which they have an archived collection of the RNA of over 500 mosquitoes collected there over a one-year period. This analysis of samples collected in the field revealed an interaction between HTV and PCLV with the dengue virus, with those mosquitoes infected with HTV and PCLV being three times more likely to also be infected with dengue.

The scientists then confirmed this observation in the controlled environment of Strasbourg’s insectarium, showing that the introduction of HTV and PCLV into laboratory mosquitoes increased replication of the dengue (DENV) and Zika (ZIKV) viruses. Higher levels of these viruses shorten the extrinsic incubation period, which is the time required for infected mosquitoes to become infectious. By using mathematical modelling, the researchers suggest that this greater infectious capacity could multiply the risk of dengue and Zika transmission by five when HTV and PCLV are present.

These findings all raise the question of the mechanism by which HTV and PCLV affect DENV and ZIKV replication. The researchers tried to find some explanations.

By studying gene expression in dengue-infected mosquitoes, in both the absence and presence of HTV and PCLV, the scientists discovered the major role of histones (proteins that combine with DNA to compact it and form chromatin), and particularly histone H4. Their findings show that the dengue virus uses histone H4 to multiply in mosquitoes. HTV and PCLV, through a mechanism that has yet to be determined, maintain the expression of histone H4 in infected mosquitoes, thereby promoting this multiplication of the dengue virus.

“A better understanding of the molecular mechanisms that govern the interaction between these three viruses seems essential for the continuation of our research. Understanding what promotes the transmission of the Zika and dengue viruses could make it possible to propose more effective strategies to reduce the transmission of the virus to humans, and to limit or even prevent epidemics,” concludes João Marques, newly recruited Inserm research director and last author of the study.

 

[1] Method of studying the genetic content of samples from complex environments taken from nature, here from mosquito samples.

[2] Sequencing of a very large number of different molecules within the same sample

[3] ZIKAlliance is a multinational and multidisciplinary research consortium of 54 partners worldwide, coordinated by Inserm. ZIKAlliance is funded by the European Union’s Horizon 2020 research and innovation program.

[4] Virus discovered by the same team during previous research.

Reproductive Life Factors and Hormone Therapy May Affect Women’s Risk of Parkinson’s Disease

Posted on by Graziella Cara

Parkinson

© AdobeStock

The specific risk factors for the development of Parkinson’s disease in women remain little studied and poorly known. Exposure to the hormones involved in female reproductive life is one of the avenues explored at the Epidemiology and Population Health Research Center (CESP) by a research team from Inserm, Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines with Institut Gustave Roussy, which compared the reproductive characteristics of nearly 1,200 women with Parkinson’s disease with those of other women from the E3N cohort[1]. Their findings show that age at first menstrual period, number of pregnancies, type of menopause and a molecule used to improve fertility are associated with a higher risk of developing the disease. This research, published in Brain, supports the role of hormonal exposures during the reproductive life of women – particularly estrogen levels – in Parkinson’s disease and opens up avenues for targeted prevention strategies.

Parkinson’s disease is a progressive neurodegenerative disease promoted by complex interactions between genetic and environmental factors. It currently affects more than 6 million people worldwide and is 1.5 times more common in men. It is also comparatively less well known and studied in women. As such, studies on certain specifically female risk factors, such as impact of exposure to the hormones related to reproductive life, whether natural (puberty, menstrual cycles, pregnancies, menopause…) or medical (hormone treatments used for contraception, to increase fertility, or post-menopause, for example), remain few in number and contradictory.

Within the Exposome, heredity, cancer and health research team at the Epidemiology and Population Health Research Center (CESP) (Inserm/Université Paris-Saclay/Université de Versailles Saint-Quentin-en-Yvelines), Inserm researcher Marianne Canonico, in collaboration with fellow Inserm researcher Alexis Elbaz, evaluated the influence of reproductive life and the use of hormone treatments on the risk of Parkinson’s disease in women. This involved examining numerous characteristics relating to the reproductive history of almost 1,200 women from the E3N cohort, in whom Parkinson’s disease was diagnosed during the 24 years of their follow-up and comparing them with those of the other women in the cohort.

The scientists were able to observe several characteristics associated with an increased risk[2] of developing the disease, the effects of which proved to be cumulative[3].

As such, those women whose first menstrual period occurred before or after 12-13 years of age showed an increased risk of +21% and +18%, respectively. However, the duration and regularity of the menstrual cycle showed no significant impact.

“It is the first time that such an association has been shown between age at first menstrual period and Parkinson’s disease, explains Canonico, one explanation for which could be – during this crucial time for neurodevelopment that is puberty – interference of the sex hormones with the neural circuits involved in the development of the disease. “

Another characteristic observed: although having or not having children was not associated with the risk of developing the disease, among those women having had children, this risk increases with the number of births (+22% with the second child and +30% starting from the third).

While being menopausal did not appear to be directly associated with an increased risk of Parkinson’s disease, the type of menopause did. Artificial menopause was found to be associated with a 28% increased risk compared to natural menopause, which is higher if it occurs before the age of 45 (+39% risk compared to menopause occurring after the age of 45) or when it is the result of both ovaries being removed – with or without the uterus[4] (+31% compared to natural menopause).

Finally, while fertility treatments were not globally associated with an increased risk of Parkinson’s disease, when looked at individually, clomiphene – used to stimulate ovulation – was found to increase the risk by 80% compared with women who had never taken fertility treatment.

In the two previous cases, exposure to insufficient levels of female hormones (estrogens) could be responsible:

“Artificial and/or early menopause causes ovarian insufficiency and consequently a sudden and anticipated fall in the levels of estrogen, which are usually still elevated before the age of 45, explains Canonico, and, as for clomiphene, it has an anti-estrogen role.” 

This hypothesis is supported by the observation of a protective effect of hormone therapies used at menopause, which appear to attenuate the risk related to early or artificial menopause for Parkinson’s disease.

“These results are consistent with the knowledge of the neuroprotective role of estrogens, which has already been demonstrated in other studies,” adds Canonico.

Although this study has the largest cohort of female Parkinson’s disease patients to date, the researchers point out that the results related to the identified risk factors must be confirmed by long-term studies with more participants. These findings could ultimately help identify groups that are at high risk, within which prevention strategies could be proposed at an early stage.

 

[1]The E3N cohort, sponsored by Inserm, Université Paris-Saclay and Institut Gustave Roussy, is the first large-scale French study on women’s health. Since 1990, nearly 100,000 French women have been followed up as part of this vast prospective study.

[2]However, breastfeeding, use of oral contraceptives, and duration of reproductive life were not found to have any association with the onset of Parkinson’s disease.

[3]A cumulative effect was observed for the risk criteria mentioned later in the text. Therefore those women having cumulated early or late puberty, several pregnancies and an artificial and early menopause had the highest risk of developing the disease.

[4]On the other hand, artificial menopause triggered by removal of just the uterus was associated with a more moderate increase in risk. 

Dietary Exposure to Nitrites Associated with Increased Type 2 Diabetes Risk

Posted on by Graziella Cara

nitrites - charcuterie

In addition to their role in food preservation, nitrites and nitrates give a pink color to ham and other processed meat products. © Adobe Stock

More than 15,000 packaged products on the French market currently contain nitrites or nitrates. Although commonly used to ensure better preservation of processed meats (ham, sausages, etc.), the safety of these food additives is the subject of debate. Nitrites and nitrates are also naturally found in various foods (particularly vegetables) and in drinking water, but agricultural and industrial practices can increase their levels.

Researchers from Inserm, INRAE, Université Sorbonne Paris Nord, Université Paris Cité and Cnam, as part of the Nutritional epidemiology research team (EREN-CRESS), studied the role of dietary nitrites and nitrates in the development of type 2 diabetes. The scientists analyzed data on the health and exposure to nitrites/nitrates of 104,168 French adults participating in the NutriNet-Santé cohort study. While their statistical analyses suggest an association between the consumption of nitrites and increased type 2 diabetes risk, no such link has been found with nitrates. Their findings have been published in PLOS Medicine.

Nitrites and nitrates are naturally present in certain foods (particularly vegetables) as well as in water and soil – a phenomenon that can be increased by agricultural and industrial practices. These compounds are therefore found in our diet.

Commonly used as additives to increase the shelf lives of certain foods such as processed meat, their antimicrobial role makes it possible to limit the development of pathogenic bacteria that cause certain food-borne infections. They also give a pink color to ham and other processed meat products. Over 15,000 packaged products on the French market currently contain added nitrites or nitrates.

This is despite recommendations by several public health authorities to limit the use of nitrites and nitrates as food additives due to their probable impact on colorectal cancer risk[1]. Although previous experimental studies had already suggested an association between exposure to nitrites and nitrates and the onset of metabolic dysfunction, epidemiological and clinical data remain sparse.

In order to learn more about the subject, a research team from Inserm, INRAE, Université Sorbonne Paris Nord, Université Paris Cité and Cnam consulted the data collected from 104,168 participants in the NutriNet-Santé prospective cohort (see box below).

The cohort volunteers had given details of their food consumption by sending the scientists full records of their meals over several 24-hour periods, including the names and brands of the products. This enabled the team to assess their exposures to nitrate and nitrite additives, with high levels of precision. In addition, this information was supplemented by control data provided by the health authorities, which shed light on the volunteers’ levels of exposure to nitrites and nitrates of non-additive origin – i.e. via water and soil – according to their location within France.

The scientists also had access to data on the medical history of the participants, their physical activity, lifestyle and health status, and their sociodemographic information. The participants studied here did not have type 2 diabetes when they joined the study, and they were followed between 2009 and 2021 to monitor for its development.

The researchers conducted statistical analyses in order to study the associations between exposures to nitrites and nitrates – in both food additive and non-additive form – and the risk of type 2 diabetes.

Those participants with a greater exposure to nitrites – specifically from food additives but also non-additive sources – presented a higher risk of developing type 2 diabetes.

In this study, there was a 27% increased risk for those with the highest consumption of total nitrites compared to those with the lowest, representing a 53% increase for those whose nitrites came mostly from additives and 26% for those whose nitrites came from other sources.

No association between exposure to nitrates and type 2 diabetes risk was found.

The results also did not support any potential benefits for dietary nitrites or nitrates in type 2 diabetes prevention.

“This is the first large-scale cohort study that suggests an association between additive nitrites and a potentially increased risk of type 2 diabetes,” explain Bernard Srour, post-doctoral researcher at Inserm, and Mathilde Touvier, Inserm research director, who led this study.

 

“These results provide new evidence in the context of current discussions on the need for a reduction in the use of nitrite additives in processed meats by the food industry, and could also support the need for better regulation of soil contamination by fertilizers. In the meantime, several public health authorities worldwide already recommend citizens to limit their consumption of food containing controversial additives, among which sodium nitrite,” conclude the two scientists.

NutriNet-Santé is a public health study coordinated by the Nutritional epidemiology research team from the Center of research in epidemiology and statistics (EREN-CRESS, Inserm/INRAE/Cnam/Université Sorbonne Paris Nord/Université Paris Cité) which, thanks to the commitment and loyalty of over 170,000 participants (known as Nutrinautes), advances research into the links between nutrition (diet, physical activity, nutritional status) and health. Launched in 2009, the study has already given rise to over 250 international scientific publications. In France, a drive to recruit new participants is still ongoing in order to continue to further research into the relationship between nutrition and health.

By devoting a few minutes per month to answering questionnaires on diet, physical activity and health through the secure online platform etude-nutrinet-sante.fr, participants in France contribute to furthering knowledge of the links between diet and health.

[1] Anses report on the risks associated with the consumption of nitrites and nitrates filed in July 2022.

A Bacterium to Protect the Microbiota from the Harmful Effect of Food Additives

Posted on by Graziella Cara

microbiote colon

Section showing the interaction of the microbiota and the intestinal epithelium in the colon. In blue, the mucus secreted by the intestinal epithelium in protection against the microbiota. In pink, the epithelial cell nuclei. © Noëmie Daniel/Inserm

Emulsifiers are food additives that are used to improve texture and extend shelf life. They are found in many processed products (ice cream, packaged cakes, sauces, etc.) despite having demonstrated harmful effects on intestinal balance. In a new study, scientists from Inserm, CNRS and Université Paris Cité at Institut Cochin in Paris sought to counteract these effects by using Akkermansia muciniphila, a bacterium naturally present in the intestine, to repopulate and thus strengthen the intestinal epithelium. The addition of this bacterium to the gut microbiota is thought to prevent the damage caused by the consumption of emulsifiers. These data, published in Gut, confirm the growing potential of Akkermansia muciniphila as a probiotic.

Emulsifiers are consumed by millions of people every day and are among the most widely used additives in the food industry. Something that is not surprising given that they improve the texture of foods and extend their shelf life. For example, emulsifiers such as lecithin and polysorbates ensure the smooth texture of mass-produced ice cream and prevent it from melting too quickly once served.

Previous studies by the team of Benoît Chassaing, Inserm researcher at Institut Cochin (Inserm/CNRS/Université Paris Cité), have shown the consumption of certain emulsifiers to lead to alterations of the gut microbiota[1] and how it interacts with the digestive system. Such alterations lead to chronic gut inflammation and metabolic dysregulation. More specifically, this research has shown the consumption of food emulsifiers to induce the ability of certain elements of the microbiota to come into close contact with the epithelium, which is the first line of defense of the digestive tract and usually sterile.

 In this new study, the researchers wanted to counteract the harmful effects caused by the consumption of emulsifiers by reinforcing the intestinal epithelium. To do this, they focused more specifically on the bacterium Akkermansia muciniphila, which, being naturally present in the intestine has already been shown to have an impact on the interactions of the microbiota with the rest of the body.

It is also known that the quantity of this bacterium is reduced when emulsifiers are consumed.

In the study, groups of mice were fed emulsifying agents as part of their diet, which for some of them was supplemented with a daily dose of Akkermansia muciniphila. The scientists saw that while the consumption of food emulsifiers was sufficient to induce the chronic inflammation associated with metabolic alterations and high blood glucose, the mice receiving Akkermansia muciniphila were totally protected against such effects. The administration of Akkermansia muciniphila was also sufficient in preventing all molecular alterations normally induced by the consumption of emulsifying agents, including the encroachment of bacteria into the wall of the epithelium.

“This research supports the notion that using Akkermansia muciniphila as a probiotic could be an approach to maintaining metabolic and intestinal health in the face of modern stressors such as emulsifiers that promote chronic gut inflammation, and the resulting harmful consequences. Furthermore, this suggests that colonization of the intestine with Akkermansia muciniphila could be predictive of individual propensity to develop intestinal and metabolic disorders following the consumption of emulsifiers: the greater the presence of the bacterium, the more likely the individual is protected from the harmful effects of food additives on the microbiota,” explains Chassaing, the last author of the study.

 

[1] All of the microorganisms – non-pathogenic (commensal) bacteria, viruses, parasites, and fungi – that live in the intestine.

Predicting the Onset of Anxiety Disorders in Adolescence Thanks to Artificial Intelligence

Posted on by Graziella Cara

Anxiété

Anxiety disorders are the most common psychiatric conditions in adolescence, with nearly one in three individuals affected. © Adobe Stock

Anxiety disorders are the most common psychiatric conditions in adolescence, with nearly one in three individuals affected. Some of these disorders – such as panic disorder or generalized anxiety disorder[1] – tend to emerge slightly later in life or consolidate in early adulthood. Therefore, identifying those who are at high risk of developing clinical anxiety (which meets specific diagnostic criteria) is crucial. For the first time, a team led by Inserm researchers Jean-Luc Martinot and Éric Artiges at the Developmental Trajectories and Psychiatry laboratory (Inserm/ENS Paris-Saclay) and the Borelli Center[2] (CNRS/Université Paris-Saclay) looked for factors that would predict the onset of anxiety disorders in adolescence. They monitored the mental health of a group of adolescents aged 14 to 23. Thanks to artificial intelligence, they have identified the warning signs most predictive in adolescence of the onset of anxiety disorders in these young adults. The results of this study have been published in Molecular Psychiatry.

A person is considered to suffer from an anxiety disorder when they experience intense and long-lasting anxiety that has no relation to an actual danger or threat, and which disrupts their usual functioning and daily activities. These disorders, which are encountered very frequently in the general population (with around 21% of adults thought to be affected at least once in their lifetime), often begin in childhood or adolescence. Therefore, being able to better identify them in these age groups would avoid worsening of the symptoms over the course of life.

While previous studies have highlighted the predictive power of artificial intelligence in psychiatric diseases such as depression and addictions[3], none had looked for predictors of anxiety disorders.

Researchers at the Developmental Trajectories and Psychiatry laboratory (Inserm unit 1299) at the Borelli Center (CNRS unit 9010) sought to detect warning signs in adolescence of the onset of anxiety disorders in adulthood.

In order to do this, the scientists monitored a group of over 2,000 European adolescents who were 14 years of age at the time of their inclusion in the Imagen cohort[4]. The volunteers all completed online questionnaires on their psychological health when they were 14, 18 and 23 years of age. Monitoring the volunteers over time made it possible to measure changes in the anxiety diagnosis.

An in-depth statistical learning study based on an artificial intelligence algorithm then determined whether some of the responses given in adolescence (at age 14) had an incidence on the individual diagnosis of anxiety disorders in adulthood (at age 18-23).

The researchers identified three major predictors or warning signs which, when present in adolescence, significantly increase the statistical risk of anxiety disorders in adulthood. These are neuroticism, hopelessness, and emotional symptoms.

 

Neuroticism designates the persistent tendency to feel negative emotions (fear, sadness, awkwardness, anger, guilt, disgust), as well as poor impulse control and poor ability to manage stress.

Despair is associated with low scores on the questionnaires evaluating optimism and self-confidence.

Emotional symptoms cover responses to the questionnaires indicating symptoms such as “headache/stomachache”; “a lot of worries, often worried”; “often unhappy, down or tearful”; “nervous in new situations, easily loses confidence”; “is easily afraid”.

 

Part of the study was also given over to observing the brains of the volunteers using magnetic resonance imaging (MRI). As brain development involves a change in the volume of different brain regions in adolescence, the researchers wanted to identify in these images a possible change in gray matter volume that could be predictive of future anxiety disorders.

While the imaging did not improve the prediction of anxiety disorders in their entirety compared to just the data from the questionnaires, it could enable a more precise determination of the type of anxiety disorder that an individual is likely to develop.

“Our study reveals for the first time that individualized prediction of the onset of future anxiety disorders in adolescence is possible. These identified predictors or warning signs could make it possible to detect people at risk earlier on and offer them an appropriate and personalized intervention, while limiting the progression of these diseases and their impacts on daily life,” explains Jean-Luc Martinot, Inserm research director and child psychiatrist, co-author of the study.

troubles anxieux

 

[1] There are several types of anxiety disorder: generalized anxiety, panic disorder, specific phobias, agoraphobia, social anxiety disorder, and separation anxiety disorder.

[2] Applied mathematics research center

[3] Whelan R., Watts R., Orr C. et al. Neuropsychosocial profiles of current and future adolescent alcohol misusers. Nature 512, 185-189 (2014).

[4] Imagen is a European cohort study that enrolled 2,223 adolescents at age 14 between 2008 and 2011. It is composed of young people from the general population and not patients.

Fathers Who Take 2 Weeks Paternity Leave Are Considered Less Likely to Develop Postpartum Depression

Posted on by Graziella Cara

 

© Photo Omar Lopez sur Unsplash

In the weeks that follow the birth of a child, both parents are likely to develop depression. Paternity leave, recognized for its benefits on family balance, child development and male-female equality, could be one of the keys to preventing this condition that affects one in ten fathers and almost two in ten mothers. Using data from over 10,000 heterosexual couples participating in the Elfe[1] cohort study, a team of researchers from Inserm and Sorbonne Université at the Pierre Louis Institute of Epidemiology and Public Health looked at the impact of two weeks of paternity leave on the risk of postpartum depression in each parent. While the findings show that fathers who have taken or intend to take paternity leave are less likely to develop postpartum depression, this risk appears to be increased in mothers whose partner has taken paternity leave. This research, to be published in Lancet Public Health, supports the importance of family policies targeted at fathers and questions the modalities of paternity leave that is beneficial to the mental health of both members of the couple.

Postpartum depression is a common phenomenon among new parents: in healthy people, 17% of mothers and more than 10% of fathers are likely to develop it in the year following their child’s birth. For some parents, the onset of a depressive episode at this crucial period in family and social life heralds the development of depressive disorders that may persist over time.

Following the European Union Work-life Balance Directive in 2019, the European Parliament has encouraged policies to promote the equal sharing of parental and domestic tasks between mothers and fathers. Paid paternity leave is considered to be one of the policies likely to meet this objective, with studies already showing a link with increased participation by fathers in household tasks and child education, that it improved dynamics within the family and the couple, and that it had positive consequences on the emotional, psychological, and social development of the child. In addition, research has shown that, among new parents, feeling socially supported and declaring oneself to be globally satisfied with their relationship with their partner was associated with a reduction in the risks of postpartum depression.

To consolidate the existing data, a research team led by Maria Melchior, Inserm Research Director at the Pierre Louis Institute of Epidemiology and Public Health (Inserm/Sorbonne Université), sought to observe the impact of taking two weeks’ paternity leave (paid and with no risk of job loss)[2] on the risks in both parents of developing depression two months after the birth of their child.

To do this, the researchers used data from the Elfe cohort study, which includes more than 13,000 French mothers and nearly 11,000 French fathers whose children were born in 2011.

Each participating couple indicated whether the father had taken or intended to take paternity leave[3]. Two months after the birth of the child, the participants all completed a questionnaire to evaluate whether they were suffering from depression. Their responses were analyzed taking into account a certain number of socioeconomic (related to employment) and family health characteristics likely to influence the use of paternity leave.

At 2 months, over 64% of the fathers had already taken paternity leave, 17% reported that they intended to take it and almost 19% had not taken and did not intend to take paternity leave. 4.5% of the fathers who took paternity leave and 4.8% of those intending to take it had postpartum depression compared with 5.7% of those who did not use it.

However, the opposite phenomenon was observed in the mothers: 16.1% of the mothers whose partner had taken paternity leave presented postpartum depression compared with 15.1% of those whose partner intended to take paternity leave, and 15.3% of those whose partner had not taken paternity leave.

Thus, while the fathers who take or intend to take two weeks’ paternity leave have a reduced risk of postpartum depression, in mothers, the taking of paternity leave by their partners does not appear to have a significant beneficial effect.

“In addition to the benefits that paternity leave can have in terms of family dynamics and child development, it could also have positive effects on the fathers’ mental health, comments Katharine Barry, Inserm doctoral student at Sorbonne Université and first author of this research. However, the negative association observed among the mothers could suggest that a two-week period of paternity leave is on the other hand not sufficient to prevent postpartum depression in mothers. “

The scientists believe that this negative association among mothers could be due to the unequal distribution of time spent on childcare, selection bias, or both.

“Despite taking many possible confounding factors into account, we were unable to sufficiently evaluate the pre-existence of depressive disorders outside of another pregnancy in the mothers. It is therefore possible that those fathers whose partner is at greater risk of depression take paternity leave more readily, explains Melchior. However, our findings underscore the importance of family policies targeted at fathers in terms of the parents’ mental health, continues the researcher, as they can advance equality of the sexes in the labor market and increase the fathers’ participation in the family sphere.  “

Future research should therefore examine the impact that the duration and timing of paternity leave may have on the mental health of parents and the development of children, including since this leave was extended in 2021.

 

[1] The French Longitudinal Study from Childhood (Elfe) is a national cohort of children followed from birth to adulthood to study the familial, economic and sociocultural factors that can influence the development of children.

[2] The average duration of paternity leave in the OECD countries in 2021. In France, paternity leave was introduced in 2002, and extended from 11 to 25 consecutive days in 2021.

[3] In this study, the participating fathers had up to 4 months after the birth of their child to take their paternity leave.

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